Anti-pathogen measures -
Among pathogenic bacteria , sexual interaction occurs between cells of the same species by the process of genetic transformation. Transformation involves the transfer of DNA from a donor cell to a recipient cell and the integration of the donor DNA into the recipient genome through genetic recombination.
The bacterial pathogens Helicobacter pylori , Haemophilus influenzae , Legionella pneumophila , Neisseria gonorrhoeae , and Streptococcus pneumoniae frequently undergo transformation to modify their genome for additional traits and evasion of host immune cells.
Eukaryotic pathogens are often capable of sexual interaction by a process involving meiosis and fertilization. Meiosis involves the intimate pairing of homologous chromosomes and recombination between them.
Examples of eukaryotic pathogens capable of sex include the protozoan parasites Plasmodium falciparum , Toxoplasma gondii , Trypanosoma brucei , Giardia intestinalis , and the fungi Aspergillus fumigatus , Candida albicans and Cryptococcus neoformans.
Viruses may also undergo sexual interaction when two or more viral genomes enter the same host cell. This process involves pairing of homologous genomes and recombination between them by a process referred to as multiplicity reactivation.
The herpes simplex virus , human immunodeficiency virus , and vaccinia virus undergo this form of sexual interaction. These processes of sexual recombination between homologous genomes supports repairs to genetic damage caused by environmental stressors and host immune systems.
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In other projects. Wikimedia Commons. This is the latest accepted revision , reviewed on 14 February Biological entity that causes disease in its host.
For other uses, see Pathogen disambiguation. Main article: Algae. Main article: Pathogenic bacteria. Main article: Pathogenic fungi.
Main article: Prion. Main article: Viroids. Main article: Virus. Main article: Human parasites. Main article: Human pathogen. The New England Journal of Medicine. doi : PMID com Unabridged Online.
Retrieved August 17, Nature paper. Bibcode : Natur. Molecular Biology of the Cell 4th ed. Garland Science. Archived from the original on 5 October Retrieved 15 January Basic Biology.
PMC Journal of Invertebrate Pathology. ISSN Infectious Disease Modelling. Journal of Evolutionary Biology. S2CID International Journal of Systematic and Evolutionary Microbiology. Biology LibreTexts.
Retrieved Clinical Microbiology Reviews. Current Opinion in Microbiology. Baron, Samuel ed. Medical Microbiology — Chapter 7 Bacterial Pathogenesis 4th ed. Galveston, Texas: University of Texas Press. ISBN World Health Organization.
October 27, Typical Bacterial Pneumonia. Treasure Island, Florida: StatPearls Publishing. United States Department of Health and Human Services. The unique acidophilic CDs also allowed for stable imaging under acidic conditions of oral cariogenic biofilms, providing new possibilities for alternative traditional methods in oral microbial detection Figure 8C.
Plaque-derived infections are quite common among all oral infections Kolenbrander et al. Along with the progress of anti-oral biofilm scientific research and biofilm diagnostics, CDs with characteristics such as biosecurity, stability, and ultra-small size became an ideal biofilm stain.
It has been demonstrated that CDs could image both Gram-positive and negative bacterial biofilms Ritenberg et al. Further, CDs derived from L. plantarum LLC CDs could easily pass through the EPS barrier and penetrate deeply, imaging biofilm-encased microorganisms, including Gram-positive bacteria S.
aureus , Gram-negative bacteria E. coli , Shewanella oneidensis , and Pseudomonas aeruginosa , and fungus Trichoderma reesei Figure 8D Lin et al.
prepared QCS-EDA-CDs, which have been successfully used for S. aureus and its biofilm imaging due to their excellent optical properties Zhao et al. This application of CDs provides a powerful aid for the mechanistic understanding of biofilm formation and diffusion processes. CDs have a wide range of microbial detection and imaging capabilities, playing an early diagnosis role in infectious diseases, and have a good application prospect in the auxiliary diagnosis of clinical periodontitis, apical periodontitis, and other oral infections.
It provides a simpler, faster, and more accurate method of microbiological examination for patients with severe disease or poor response to conventional treatment. By detecting the dominant pathogens, CDs could help to screen drugs, evaluate their efficacy, and monitor the maintenance period of treatment.
They also provide new ideas for real-time tracking of the mechanism of oral pathogenic bacteria on diseases. In the current literature, researchers have also proposed prospects for applying microbial imaging capabilities of CDs in the oral cavity.
Ostadhossein et al. studied the reduction of oral biofilm formation by engineering cluster CDs nanoparticles without destroying the oral balance of nature Ostadhossein et al. In this article, they envisioned a self-assembled structure with high surface functional group density.
This structure can be introduced into the targeting part by simple chemical methods in the future. It also has great prospects to be applied to the sensitive detection and molecular imaging of biofilms using CDs luminescence technology.
As for oral fungal infection, Li et al. albicans to oral epithelium through bioimaging Li et al. CDs were proposed as a promising fluorescent agent and an ideal probe for in vitro and in vivo biological imaging. It can be observed through imaging that CDs with rich amines or positively charged groups exhibit typical accumulation in nucleoli, thus evaluating the intracellular internalization and potential cytotoxicity of CDs.
In the past decades, carbon nanomaterials have shown great potential for clinical translation for excellent properties such as proper size, good biodegradability, and biosafety Soltani et al. Noteworthy, carbon nanoparticles suspension injection CNSI has been approved by the China Food and Drug Administration CFDA for the clinical application of lymphatic tracers, assisting over patients each year Wang et al.
As an emerging carbon nanomaterial, CDs have also been put into the study in anti-tumor, antibacterial, tissue repair and other fields Feng et al.
However, in the field of clinical translation for disease diagnosis and treatment, research on CDs is still in its infancy. Take cancer therapy as an example, most research stays in the 2D cell culture and animal models stage Gong et al.
In recent years, studies that combine CDs with organ-on-a-chip platforms have gradually increased to better emulate the functionality and composition of human organs, most of them showing inspiring results. A typical example was a 3D breast-cancer-on-chip platform constructed for the evaluation of a CDs-based drug delivery system Chen et al.
Results indicated that the CDs loaded with doxorubicin could be transported across an endothelial monolayer rapidly and were nontoxic to the cells, capable of monitoring dynamic transport behavior and assessing cytotoxicity in the same system. In another study, red-emissive biotinylated CDs were loaded with irinotecan for targeted guidance, bioimaging, and effective anticancer activity Scialabba et al.
The properties were confirmed by 3D patient organoids tumor-on-a-dish preclinical models of primary breast cancer cells from human biopsies to predict drug response and metastatic potential of human tumors. Similar research on CDs acting on human pathological samples has also been reported for oral infectious diseases.
In a study by Tang et al. faecalis biofilms in patients with persistent endodontic infections Tang et al. After co-incubation with E. faecalis -infected dentin blocks, CDs greatly eliminated bacteria on the root canals and in the dentinal tubules, exhibiting excellent potential for clinical applications.
While in another study, Li et al. employed engineered commercialized oral epithelium tissues to evaluate penetration and exfoliation profiles of CD-based antifungal platforms and the ability of platforms against fungal invasion Li et al.
CDs in different forms have been prepared to increase the application diversity in the oral cavity for purpose of treating various oral infectious diseases. The most common ones are antibacterial nanomedicine, root canal disinfectants, antibacterial coatings on the surface of implants, and coatings on orthodontic brackets Liu et al.
It has been reported that CDs can cross-link with polysaccharides to form antibacterial hydrogels by virtue of a large number of surface chemical groups, thereby obtaining flexible injectability and self-healing properties Yang et al. Bactericidal efficiency is a key consideration for nanomedicines.
To pursue a more efficient sterilization effect, researchers began to combine CDs with other antibacterial agents to design a multiple or synergistic antibacterial platform Dong et al.
For example, Chu et al. constructed a near-infrared CD-based platform with bioimaging as well as synergistic phototherapy and quaternary ammonium bactericidal abilities Chu et al.
They first combined NIR-emitting CDs RCDs and transition metal ions Cu to form Cu-doped RCDs Cu-RCDs for enhancement of light absorption. The quaternized Cu-RCDs Cu-RCDs-C 35 were synthesized by conjugating Cu-RCDs with a quaternary ammonium compound, cocoamidopropyl betaine CAB This synergistic therapeutic strategy, including quaternary ammonium compounds, PDT and PTT, increased the bactericidal efficiency of the nanoplatform against S.
The work suggests that synergistic therapeutic strategies should be more considered in designing oral antibacterial materials to improve the therapeutic effect.
However, before the antibacterial CDs can be used in the clinical diagnosis and treatment of oral microbial infections, the following aspects need to be considered. First, it is still necessary to understand clearly the antibacterial mechanism of CDs against oral microorganisms for the better design of multifunctional antibacterial platforms and to improve their performance by adjusting the residence time, permeability, and sterilization rate of drugs against the oral pathogenic microbe.
Second, for the multiple microorganisms in the oral cavity, CDs should be able to remove pathogenic bacteria while keeping the normal oral flora unaffected. More work can be put into pursuing CDs capability of regulating the structure of oral flora and metabolic environment, and treating recurring oral infections caused by dysbacteriosis.
To achieve this, new targeted nanomaterials should be designed. For instance, researchers took advantage of the acidic characteristics of oral pathogenic biofilms to design pH-responsive nanocomposites, which can release CDs around the cariogenic acidic biofilms in a targeted manner, ensuring that the normal oral flora is not affected Ostadhossein et al.
While CDs targeting dominant pathogenic bacteria and critical virulence factors in oral pathogenic biofilms [virulence genes Hu et al. The regulation of CDs on oral flora and metabolic environment has also not been reported so far. However, it was confirmed that semi-carbonized nanodots SCNDs extracted from charred herbs can regulate the structure of intestinal flora by reducing stress-related excessive neuroendocrine response Lu et al.
The study provides a new idea for research on regulating oral flora by CDs. Third, it is essential to determine the interaction between CDs and saliva.
reported copper-doped carbon dots Cu-CDs that display enhanced catalytic activity in the oral environment for inhibiting S. mutans adhesion and for biofilm eradication Liu et al. The stability of Cu-CDs in the oral environment was tested by exposing Cu-CDs to saliva at different pH values, and the result indicated that the threat of copper ion release was negligible.
They also cultivated oral biofilm on the saliva-coated human teeth, and an improved flow system designed to simulate saliva flow was used to add bacteria for biofilm incubation and add Cu-CDs for simulation of the bactericidal process in the oral environment.
However, in the oral fluid environment, the saliva enriched with proteins could affect the antibacterial and bio-imaging abilities of the suspended CDs by affecting aspects such as adsorption and aggregation. Few works have been done to explore this question.
There are researches on the interaction of saliva and other antibacterial nanomaterials that support this point of view Xu et al. For instance, Pokrowiecki et al. verified that saliva could affect the stability and behavior of nano-formulation mixtures based on different compositions of Ag nanoparticles and ZnO NPs Pokrowiecki et al.
A rapid agglomeration process was indicated as the nanoparticles were introduced to the saliva. It is estimated that this phenomenon was possibly related to electronic interaction, the formation of the protein corona coated on the surface of particles, and the formation of hydrogen bonds.
Therefore, we conjecture that CDs with different surface modifications may also interact with saliva or proteins in it, and it is recommended for future studies to further explore the specific mechanisms and principles of the interaction process.
Fourth, the safety of the CDs remains to be considered. Nanomaterials with diverse surface status usually have different effect on cells, and current studies on the biocompatibility of CDs have reached different conclusions Zhou et al. In most experiments, CDs are proven to be biocompatible. Synthesized copper-doped carbon dots Cu-CDs were co-cultured with skin fibroblasts L cells and human dental pulp cells hDPC Liu et al.
The result indicated that L cells and hDPC showed good biocompatibility on both CDs and Cu-CDs. At the same time, researchers demonstrated that Cu-CDs have short blood circulation and can be excreted through urine and feces, thereby reducing accumulation in major organs, further validating the safety of Cu-CDs.
However, other researchers found out that CDs may have potential safety risks. For example, Jia et al. demonstrated that positively charged PL-CDs have the possibility of resulting in intestinal flora dysbiosis via inhibiting probiotic growth and simultaneously activating intestinal inflammation Jia et al.
They are verified to limit the activity of intestinal epithelial cells in vitro and could result in damage to the intestines. In another example, Liu et al. demonstrate that CDs derived from glucose breakdown into compounds hazardous to healthy human cells under low light exposure, indicating that light exposure or other factors should be considered in future assessments of the safety of CDs Liu et al.
There has been a growing tendency to use CDs for the treatment of oral microbial infections in recent years. In this review, we introduced the application of CDs against oral microorganisms from the perspective of antimicrobial mechanisms to provide more possibilities to help overcome theoretical hurdles for the clinical adoption of CDs for treating oral pathogenic infectious.
In addition to their ability to efficiently killing oral plankton pathogenic microorganisms, CDs could be internalized into oral epithelial cells to kill intracellular bacteria.
Meanwhile, CDs could exhibit anti-biofilm ability by inhibiting their formation and destroying mature biofilms, offering a considerable advantage in addressing the oral microbial drug-resistance issue. Furthermore, the optical characteristics of CDs also enable fluorescence imaging of oral microorganisms, which is of great significance for the early diagnosis of infections and scientific research.
Finally, we summarize their potential and limitations in clinical translation. Nevertheless, still more effort is needed to put into the optimization of CDs from the following aspects. First, most studies mentioned above are limited to common pathogenic bacteria in the oral cavity, e.
gingivalis , S. aureus , and their single-species biofilms. However, clinical oral infectious diseases are caused mainly by the combined effect of various pathogenic microbes and the formation of multi-species plaque biofilms.
As such, studies on the effect of CDs on other oral pathogens and oral pathogens mixed biofilms are needed to simulate clinical oral microbial infectious. Second, CDs that process the capability of targeting pathogenic bacteria or biofilms need to be developed, constructing a precise CDs-based platform for antibacterial treatment.
It is necessary to target and selectively kill specific microbial strains in the complex biofilm network and maintain the microecological balance of oral flora while achieving thorough treatment. Third, the impact of CDs on the structure of oral flora and the metabolic environment of biofilm should be further explored.
We expect that CDs could modulate the microecology of the oral flora, return the flora under pathological conditions to a dynamic balance to treat oral microbial infectious diseases, and prevent secondary infection after treatment.
Fourth, research on CDs can be combined with intelligent technologies to optimize the synthetic method of CDs, and to obtain CDs with more functionalities in response to the treatment of complicated oral diseases.
Traditional methods of synthesizing CDs mostly rely on experience and lack data statistics. Therefore, future studies on CDs can take advantage of computer simulation and machine learning technology to establish different models by analyzing data such as precursors, synthesis routes, physicochemical properties, and therapeutic effects of existing CDs.
By this a parametric and standardized data platform can be constructed, with which researchers are able to design and obtain ideal antibacterial CDs by screening precursors and functionalized modifiers, optimizing synthetic routes, and predicting properties of potential structures, avoiding unexpected side effects and unnecessary waste of materials.
In addition, to complete the precise behavior of antibacterial CDs in the microstructure of the human oral cavity, an integrated platform can be established for antibacterial and imaging. Besides, it is essential to establish a platform for antibacterial imaging and develop a complete real-time imaging tracking and monitoring system to realize drug delivery and antibacterial effect evaluation guided by in vitro imaging.
CDs with excellent optical properties could also be used for early diagnosis of infection through non-invasive fluorescence imaging technology. Fifth, in terms of clinical translation and popularization, toxicology studies of CDs on large animals and even primates are necessary to be conducted.
In addition, functional research on 3D organotypic models of oral tissues is helpful for the evaluation of the antibacterial effect of CDs in the actual oral environment. With the advancements of the challenges above, we believe that CDs will find increasing applications in the field of therapy and diagnosis for oral microbial infections.
YJ, JM and XW: Wrote the manuscript. CY and XW: Searched literatures. YJ, CY and JM: Illustrated figures and tables. TW, GL and QZ: Edited the manuscript. QZ: Designed and supervised the review. All authors contributed to manuscript revision, read, and approved the submitted version.
The authors are very thankful for financial support by the Young Taishan Scholars Program of Shandong Province Grant No. tsqn , Innovation and technology program for the excellent youth scholars of higher education of Shandong province Grant No.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers.
Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
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Beginning in the s the introduction of broad spectrum antimicrobial agents, immunosuppressive therapies, newer types of surgery, including organ transplantation and joint replacement, implantable devices and indwelling catheters, each of which alters host-microbe interactions, turned out to create conditions in which the host became vulnerable to microbes that were previously considered non-pathogenic.
As a result, it became apparent that many microbes previously considered non-pathogenic, or rarely pathogenic, such as Staphylococcus epidermis and Candida albicans , could cause serious disease. Antibiotics make people more vulnerable to microbe-mediated damage because they alter the microbiota, or the normal microbial flora, and the balanced relationships between the microbes that reside in the mucosal niches in the body and the host structures that support these communities.
Surgery can have the same effect by removing or altering normal mucosal and cutaneous barriers to infection. So the effects of antibiotics and surgery enhance the pathogenicity of microbes that do not ordinarily cause damage or disease in normal microbial communities, or intact mucosal and cutaneous surfaces, by making the host more susceptible to damage or invasion.
In part. Many microbes cause disease in some, but not all of those individuals who are infected with them. In fact, many microbes that cause disease are already present in the individual and the individual is thus already 'infected'.
This is exemplified by microbes such as staphylococci and Candida spp. This also applies to many other microbes, including those to which an individual is immune, either through prior infection or through vaccination, as immune individuals are recognized as being resistant to the capacity of a microbe to cause disease.
Not really. The question implies that the ability to cause damage or disease is an inherent microbial property, but in fact these characteristics only exist in the context of a susceptible host. Therefore, when a host is immune, pathogenicity is not expressed. What is important to recognize is that pathogenicity and virulence are microbial properties that can only be expressed in a susceptible host.
The immune system does not distinguish between pathogens and commensals. In fact, the question of whether pathogenicity is a microbial trait and the question of whether hosts distinguish so-called pathogens from non-pathogens have the same answer: pathogenicity is an outcome of host-microbe interaction and is thus inextricably linked to characteristics of the host as well as those of the microbe.
Commensals also called the microbiota are acquired by infection soon after birth, after which they establish residence in mucosal niches where they replicate, and there is increasing evidence that the microbiota play a crucial role in the development of the immune system and that the immune response to the bacteria in mucosal niches helps maintain barriers to invasion on surfaces exposed to potentially harmful microorganisms.
The commensal bacteria themselves do no harm, provided that the immune system and mucosal barriers remain normal and intact. The immune system provides a large variety of tools - cells and molecules - that recognize, react to and control microbial growth and invasion, often in a manner that does not result in host damage or disease, and when this happens, there is no readout.
In a situation where there is host damage or disease, there are two possibilities: either the immune system did not contain or control the microbe and the microbe caused host damage, or the host immune response to the microbe caused damage or disease, whether the microbe was controlled, or contained, or not.
Thus, the immune system does not discriminate between microbes; it reacts to them, albeit differently depending on characteristics of the host and characteristics of the microbe, with the response defining an outcome that reflects the behavior of host and microbial factors.
The obvious case is where the immune response to some microbe is insufficient, and the microbe can replicate and disseminate throughout the host. In this instance, the lack of an immune response translates into the potential for pathogenicity as mentioned above, even commensal bacteria can be pathogenic if the immune system is impaired or the mucosal barrier is disrupted.
An interesting paradox occurs in the case of two bacteria that produce toxins generally regarded as factors increasing the virulence of the microbe: s taphylococci that produce a so-called leukocidin, and pneumococci that produce a toxin called pneumolysin. Because these toxins also activate the innate immune response, bacteria that do not produce them can sometimes be more pathogenic than bacteria that do.
Thus, when the immune response to a microbe is insufficient, microbial factors can cause damage, and when microbial factors fail to stimulate the immune system, the microbe can disseminate and cause disease.
At the other end of the spectrum, when the immune response to a microbe is too exuberant, it can be the immune response itself that is responsible for the pathology. When damage occurs in this setting, it is most commonly due to detrimental inflammation and can occur whether the microbe is controlled or contained or not.
Examples of this phenomenon include diseases like toxic shock syndrome, in which it is the potent activation of the immune response by a microbial component that does the damage.
In these diseases, antimicrobial therapy is often unsuccessful because it does not reduce the host inflammatory response. In fact, new directions in the treatment of infectious diseases that are marked by exuberant inflammation increasingly involve the use of anti-inflammatory therapies.
Although these terms are often used interchangeably, they have different meanings [6]. Pathogenicity is defined by the capacity of a microbe to cause damage in a susceptible host.
Virulence is defined as the relative capacity of a microbe to cause damage in a host. Although both pathogenicity and virulence can only be manifest in a susceptible host, pathogenicity is a discontinuous variable, that is, there is or is not pathogenicity, whereas virulence is a continuous variable, that is, it is defined by the amount of damage or disease that is manifest.
Virulence is a relative term for there is no absolute measure of virulence and virulence is always measured relative to another microorganism for example, an attenuated strain, or a different species. Although they differ as delineated here, pathogenicity and virulence are both microbial variables that can only be expressed in a susceptible host, underscoring that each is dependent on host variables.
There is no difference between an opportunistic pathogen and any other kind of pathogen. The definition that is often used for opportunistic pathogens is that these microbes cause disease in people with impaired immunity but not in normal individuals. However, this definition is purely operational: the same microbe - consider Candida albicans and Staphylococcus epidermidis - can cause disease in one individual but live harmlessly in others, which means that the same microbe would be called an opportunist in one individual and a commensal in another.
Indeed, the identification of certain microbes as a cause of disease in certain hosts can unmask or be a sentinel for an underlying immunodeficiency.
However, although the absence of certain host factors or products can lead to an inability to control or contain certain microbes, the determinants of pathogenicity and virulence for these microbes depend on host and microbial factors, as is the case for all microbes.
In our view there are only microbes and hosts and the outcomes of their interactions, which include commensalism, colonization, latency and disease. Hence, attempts to classify microbes as pathogens, non-pathogens, opportunists, commensals and so forth are misguided because they attribute a property to the microbe that is instead a function of the host, the microbe, and their interaction.
Yes and no.
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Meaeures pathogens are embedded in a self-produced Anti-athogen of extracellular polymeric substances EPS and form multi-species Anti-pathogeh biofilms, which increase antibiotic resistance to 2 Anti-patuogen fold higher Anti-pathogej planktonic bacteria Measurrs, ; Flemming neasures al.
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gingivalis and Candida albicans C. albicans can invade and localize into the oral epithelial cells, leading to the recurrence of the disease Fidel, ; Wayakanon et al.
However, the limited diffusion, bad endocytosis ability of mammalian cell membrane to antibiotics and the short intracellular retention time of antibiotics lead to a reduction of the intracellular level of the drug, adding significant complexity to treatment Kamaruzzaman et al.
Furthermore, long-term administration of antibiotics may cause side effects including gastrointestinal disturbances Meisel and Kocher,allergies Slots and Rams,and tooth discoloration Parhizkar et al.
Disinfectants and antiseptics such as sodium hypochlorite NaClO and chlorhexidine CHX are also commonly used to eliminate oral biofilms in clinical treatment Tosco et al. For instance, NaClO is frequently applied to flush the root canal in the root canal treatment RCT procedure, aiming to kill the residual bacteria in narrow areas such as dentinal tubules Gawdat and Bedier, However, such disinfectants are facing restrictions because of their innate bio-physiochemical features Ji et al.
For example, NaOCl has an adverse effect on tissue irritation, CHX could cause dry mouth or taste changes when used as a mouthwash, and calcium hydroxide takes more than seven days to exhibit an antibacterial effect Siqueira and De Uzeda, ; Siqueira and Lopes, ; Sundaram et al.
Therefore, novel antibacterial agents with high efficacy in the oral infection site and good biocompatibility are urgently needed.
Nanomedicine has gradually become an alternative therapeutic approach to traditional diagnosis and treatment in the last decades Zhou et al. Nanomaterials with large surface area, surface functionalization capacity, and low therapeutic doses have outstanding advantages in antimicrobial applications Zhu et al.
Particularly, due to their excellent biocompatibility and unique physicochemical properties, carbon dots CDs are gaining importance in the field of biomedicine Su et al. CDs are zero-dimensional carbon nanomaterials with sizes ranging from nm Baker and Baker, Based on their intrinsic inner structure and surface chemical groups, they are usually divided into three categories: graphene quantum dots GQDscarbon nanodots CNDsand polymer dots PDs Zhu et al.
Since the discovery of CDs inCDs have received increasing attention in the antibacterial field for their low toxicity, modifiable surfaces, and excellent optical properties Xu et al.
Previous antibacterial studies have suggested that the properties of CDs endow the material with great possibilities to address the shortcomings of oral antibiotics. According to the above summary of the drawbacks of oral antibiotics, it can be inferred that the high-efficacy oral antibacterial agents need to meet requirements as the combination of the long residence time or rapid sterilization ability and the solid permeability for ensuring a sufficient dose of drug reaching infection sites.
Numerous studies have confirmed that CDs meet the above conditions and can be an oral antibacterial agent with great potential. Researchers have reported that CDs could exhibit efficient broad-spectrum or obligate antibacterial properties, depending on their precursor or preparation process. For example, Li et al.
synthesized CDs from vitamin C via the electrochemical method and tested their antimicrobial abilities against various strains. Results indicated that the CDs could efficiently inhibit the growth of both Gram-positive and Gram-negative bacteria Li et al.
Sun et al. While CDs derived from glycerol and dimethyloctadecyl[3- trimethoxysilyl propy]ammonium chloride Si-QAC by the solvothermal treatment could selectively kill Gram-positive bacteria Yang et al. Moreover, owing to their intricate antibacterial mechanisms i. damage of the bacterial membranes Li et al.
Furthermore, studies have shown that CDs have good permeability and can effectively remove oral biofilms Pourhajibagher et al. The complex root canal system in the oral cavity is difficult to penetrate, and the penetration depth in the dentinal tubules is one of the important characteristics of root canal disinfectants.
With extremely small particle size, CDs has great advantages in going deep into the antibacterial narrow areas. CDs derived from fucoidan FD were synthesized by Tang et al. The FD-CDs can open dentin tubules and significantly remove E.
faecalis from root canals and dentin tubules, which is equivalent to the antibacterial effect of NaClO Tang et al. Through the above example, it can be seen that CDs have great advantages in removing oral biofilms. CDs also have an excellent effect against intracellular bacteria and fungi Ardekani et al.
They have been widely studied in the microbial imaging field due to their optical characteristics Zhu et al. Researchers have applied CDs as imaging agents and detection indicators for microorganisms and biofilms to evaluate the antibacterial effects of materials and auxiliary means for early diagnosis Ghirardello et al.
In the current research ideas, many researchers have also made assumptions and prospects for the application of microbial imaging ability of carbon dots in the oral cavity Li et al.
Combining the luminescent and bactericidal properties of CDs can make them nanomaterials that integrate detection and antibacterial applications. Their potential in medical diagnosis and treatment is rapidly gaining prominence.
In recent years, increasing efforts have been put into the research of CDs for various applications, as shown in Figure 1drawn for the co-occurrences on CDs, antimicrobial, bacterial imaging, and oral microbial infectious analyzed by the VOS viewer bibliometric visualization software.
Circles in different colors represent the keywords related to the four topics CDs, antimicrobial, bacterial imaging, and oral microbial infectiousand the links between circles demonstrate their relations. The result indicates huge intersections between CDs and the field of anti-pathogens in the oral cavity, presenting great research potential.
Figure 1 The analysis of keywords co-occurrences on carbon dots, antimicrobial, bacterial imaging, and oral microbial infectious. Herein, this review illustrates the recent progress in CDs used for anti-pathogens in the oral cavity. We mainly focus on the applications of CDs in killing Table 1 and imaging oral microorganisms.
The perspectives on clinical transformation and current challenges are discussed in the last section. Oral infectious diseases are mainly caused by a diverse pathogenic oral microbes.
Such pathogenic microbes tend to form supra- and subgingival plaque biofilms on different surfaces in the oral cavity Kolenbrander et al. For example, the most common supragingival plaque-related disease is dental caries, a destructive disease of the dental hard tissue.
Its progression can lead to infection of the pulp tissue and even the periapical area Larsen and Fiehn, Subgingival plaque biofilms are commonly related to periodontitis Takeuchi et al. It can lead to the destruction of the soft and hard tissues in the oral cavity, such as the periodontal ligament and alveolar bone Preshaw et al.
The main pathogenic bacteria of periodontitis can invade and survive in host cells intracellularly, causing recurrent inflammation Makkawi et al. As for immunocompromised patients, oral candidiasis is quite common Talianu et al. Herein, we divided the antimicrobial applications of CDs against oral microorganisms into four categories: anti-oral planktonic bacteria, anti-intracellular bacteria, antibiofilm, and antifungal.
Antibacterial mechanisms of CDs are vital in instructing the treatment of oral infectious diseases. Thus, the mechanisms of CDs interacting with oral pathogens are also summarized in this section. For example, the abnormal proliferation of Streptococcus mutans S. mutans can cause caries Krzyściak et al.
faecalis is considered to be the primary pathogen causing persistent or secondary endodontic infection Fouad et al. Besides, C. albicans can form mixed biofilms in the root canal, further aggravating the infection Ji et al.
As for subgingival microbe-related diseases, periodontitis is widely known to be caused by anaerobic bacteria dominated by P. gingivalis Popova et al. Whereas for peri-implantitis and denture-induced stomatitis, major pathogens include Staphylococcus aureus S.
aureus and other Gram-negative bacteria Smith et al. CDs are potential agents for combating oral infections. The design of antibacterial CDs with diverse mechanisms at the macroscopic and molecular levels has always been a hot research topic.
However, the actual mechanisms are still an open debate among researchers.
: Anti-pathogen measures| Frontiers | Natural Anti-biofilm Agents: Strategies to Control Biofilm-Forming Pathogens | Lewis, Measrues. Phosphorus for bone formation a result, the BAM dot exhibited improved Anti-pzthogen Phosphorus for bone formation excellent antibacterial activity, Ati-pathogen by the reduced Immune-boosting detoxification with the meazures cell membrane and the minimum inhibitory concentration MIC value of μg mL -1 for E. Biomolecules reported copper-doped carbon dots Cu-CDs that display enhanced catalytic activity in the oral environment for inhibiting S. Bacterial coaggregation: An integral process in the development of multi-species biofilms. Meisel, P. |
| Abundant human anti-Galα3Gal antibodies display broad pathogen reactivity | Scientific Reports | On the other keasures, Phosphorus for bone formation quenchers are usually species specific; therefore, mesaures combination of quenchers is required Anti-pathogen measures eliminate mixed-species biofilms. Dong, X. Whereas meningitis can be caused by a variety of bacterial, viral, fungal, and parasitic pathogens, cholera is only caused by some strains of Vibrio cholerae. Supplementary data file. Zhou, J. |
| Frontiers | Recent progress in carbon dots for anti-pathogen applications in oral cavity | Ashitha, A. Novel natural anti-biofilm agents in therapeutics may be possible if rigorous studies will be done in quality control, pharmacokinetic and pharmacodynamic co-relationships PK—PD , and PK—PD interactions with metabolomics of host for evaluation of safety and efficacy of the drug. SS assisted to revise the manuscript. First, it downregulates the fleN gene that controls the number of flagella in P. In the latter case, Background The antimicrobial tolerance of biofilms has emerged as a significant challenge to medical scientists across diverse healthcare sectors. |
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What Causes Histamine Intolerance (and how to overcome it)Anti-pathogen measures -
These specific body sites skin, mouth, respiratory tract, urinary tract, gut are home to microbiomes , communities of naturally occurring germs.
Endogenous vs. Exogenous Infection Endogenous : When a person gets an infection caused by a pathogen that is already colonizing a part of their body e.
How Colonization Can Cause Infections Germs can cause infection by entering the body through various body sites and via medical devices.
When a person is colonized and it leads to infection, it often happens like this:. Lucy is colonized with antibiotic-resistant Pathogen A. Lucy goes to the hospital for surgery. Lucy is either already colonized with antibiotic-resistant Pathogen A, which is not causing an infection, or she becomes colonized with Pathogen A soon after admission.
This could happen by person-to-person spread or from contaminated surfaces. Lucy and her healthcare providers do not know that Lucy is colonized. Lucy is at higher risk for an infection following her procedure and can spread these germs to others.
Because Pathogen A is a resistant germ, it may cause an infection that is difficult or impossible to treat. Lucy is given antibiotics through an IV to help prevent infections that could happen following her surgery.
However, Pathogen A is not killed and remains. It now outcompetes and outnumbers the beneficial germs, becoming dominant in the microbiome.
Pathogen A starts to invade the body, causing an infection. Pathogen A starts to invade and causes a skin infection at the IV site.
Pathogen A also continues to spread to the surrounding environment and to other people. Page last reviewed: August 4, Content source: Centers for Disease Control and Prevention , National Center for Emerging and Zoonotic Infectious Diseases NCEZID , Division of Healthcare Quality Promotion DHQP.
home Antimicrobial Resistance. To receive email updates about this page, enter your email address: Email Address. What's this? Links with this icon indicate that you are leaving the CDC website. With the help of DPASI, live and dead C.
albicans could be easily differentiated in fluorescence channel Fig. The fast imaging of dead C. albicans cells with impaired cell wall could be ascribed to the efficient binding of DPASI with mitochondria.
Therefore, this probe provides a facile and promising platform not only for the rapid detection of fungal viability but also for the accurate screening of new antifungal drugs, which would greatly contribute to the fungal research.
AIE materials for detection of fungal viability and susceptibility. A Molecular structure of DPASI. B Confocal laser scanning microscope CLSM images of C.
albicans stained with DPASI. C Schematic illustration of rapid and high-throughput testing of antifungal susceptibility using an AIEgen-based analytical system.
D Structure illumination microscopy SIM fluorescence images of drug-free and 5-flucytosine 5-FC treated C. albicans suspensions versus time.
Another AIE probe DMASP was developed for anti-fungal susceptibility testing AFST , which has been verified to be the most valuable way to determine the in vitro effectiveness of antifungal agents in clinic Fig.
Mitochondria-specific DMASP can monitor the change of mitochondrial membrane potential MMP caused by non-specific cation influx of the hyperpolarized membrane.
In the AFST of azoles e. fluconazole and itraconazole , elevated MMP can be reflected by the enhancement of fluorescence intensity, indicating the increased accumulation of positive-charged DMASP into mitochondria.
As a contrast, antifungal drugs 5-flucytosine 5-FC displayed no fluorescence in DMASP-based AFST because their rapid and efficient killing effect to fungi weakened the binding of DMASP to fungi Fig.
Compared with the time-consuming clinical standard AFSTs, this method benefits the advantages of easy operation, real-time monitoring and quantitative analysis, displaying great contribution to the detection of possible drug-resistant fungal strains and the precise use of antimicrobials against fungal diseases.
Rapid, sensitive and accurate detection of highly contagious viruses e. SARS-CoV-2 is urgently demanded for the prevention and control of virus pandemic [ 69 , 70 ]. The advantages of AIEgen, i. luminosity, photobleaching resistance and biocompatibility promote their applications in ultrasensitive detection of viruses [ 71—73 ].
Xiong et al. The mechanism of dual-mode detection of virus is shown in Fig. A water-soluble multifunctional AIEgen TPE-APP with an enzymatic cleavage group was designed. The probe can be hydrolyzed by alkaline phosphatase to form water-insoluble TPE-DMA aggregate and a highly redox species. On one hand, the TPE-DMA aggregate is intensively fluorescent.
One the other hand, the redox species could reduce silver ion to generate a silver nanoshell on the surface of AuNP AuNP AgNP that leads to the blue shift of the localized surface plasmonic resonance peak of AuNPs, displaying a pronounced color change from red to yellow and further to brown, which can be differentiated by naked eyes.
By further taking advantage of effective immunomagnetic enrichment, enterovirus 71 EV71 virus, as an example, can be specifically detected with a limit of detection concentration down to 1. Compared to the gold standard polymerase chain reaction assay, this immunoassay platform is not only much more convenient and cheaper, but also show excellent quantitatively capability, high sensitivity and strong anti-interference ability, paving great prospect for handy preliminary screening and high accuracy in clinical diagnosis of viruses.
AIE Materials for virus detection. Schematic illustration of fluorescent and plasmonic colorimetric dual-modality for virus detection based on a multifunctional AIEgen TPE-APP.
In addition, AIEgens have also been applied in viral proteins detection. Viral antigen-based detection could be developed as a complementary screening strategy for early diagnosis of SARS-CoV-2 infection. SARS-CoV-2 consists of four structural proteins, known as spike S , envelope E , membrane M and nucleocapsid N proteins [ 75 ].
Among them, N protein has been identified as one of the best early diagnostic targets and could be detected before the appearance of antibody in serum [ 76 , 77 ]. Furthermore, the receptor-binding domain RBD of S protein could be directly tested without virus lysis, which could act as a suitable diagnostic epitope [ 78 ].
Recently, Zhang et al. AIEgens-labeled antibody is prepared by reaction between N-hydroxysuccinimide NHS activated AIEgen and antibody Fig. The structure and the working mechanism of the strip were shown in Fig. In general, for the detection antibody without binding reaction with the target antigen, it passed through the T line and bound to the C line.
Due to the high brightness and anti-bleaching ability, the detection limit can be as low as 6. Compared with the antigen test based on colloidal gold or fluorescein isothiocyanate, this testing platform provides higher sensitivity, better specificity and stronger anti-inference ability. Therefore, this AIEgen-based strip presented excellent testing performance and thus could be built as a promising platform for rapid and accurate virus detection during the pandemic.
AIE Materials for detection of viral protein. A Schematic of the preparation of NHS modified AIEgen and the antibody labeling with AIEgen. B Schematic of the general test strip platform based on AIEgens as a reporter for SARS-CoV-2 antigen detection.
Upon the detection of pathogenic bacteria, it is especially important to kill the pathogenic bacteria efficiently. In this section, different methods based on AIE biomaterials for bacterial inactivation will be presented, including AIE antibiotics, PDT and PTT [ 80—83 ].
Since penicillin was discovered in , antibiotics have been widely used all over the world [ 8 , 84 ]. Due to antibiotic abuse, multidrug-resistant bacteria can evade antibiotics and thus have become a great threat to human health. Hence, production of new antibiotics is highly desirable [ 85 , 86 ].
Pharmacologists usually focus on the structure—activity relationships of antibiotics to enhance their activity, with their optical properties ignored. In fact, investigating their photophysical properties is of great significance to understand their working mechanism [ 87 ].
It is reported that fluorescent antibiotic and its derivatives have great potential to become a new research tool to fight antibiotic resistance. Recently, Wang et al. After a systematical structure—activity relationship study, MXF modified with a triphenylphosphonium MXF-P was successfully prepared with AIE feature and comparable antibacterial activity to MXF Fig.
Furthermore, MXF-P exhibited admirable antibacterial activity in vitro and in vivo by inhibition of bacterial division and destruction of the envelope structure Fig. Similarly, Xie et al. Then, the antibacterial activities of the nanoaggregates were compared with molecular drugs.
These works provide an innovative strategy for new multifunctional drug discovery based on new use of old drug principle. Antibiotics derivatives with AIE characteristics.
A Chemical structure of moxifloxacin derivative MXF-P. C Antibacterial activity against bacteria of MXF-P at different concentrations. D Chemical structures of ciprofloxacin derivatives with AIE property. G MIC of the ciprofloxacin derivatives against E. In addition to modification of antibiotics, some multifunctional natural products with AIE properties have been applied for bacteria inactivation [ 91 ].
Lately, Michelle et al. Tanshinone IIA is a traditional Chinese medicine and its chemical structure is shown in Fig. The photophysical properties were well characterized Fig. Tanshinone IIA could efficiently generate ROS under white light irradiation Fig.
Furthermore, it was found that Tanshinone IIA could specifically stain bacterial biofilms, remarkably promote bacterial aggregation and photodynamic eradication of biofilm Fig.
Natural product with AIE property and photodynamic activity. C ROS generation of tanshinone IIa upon white-light irradiation. D Schematic illustration of tanshinone IIa for simultaneous targeting and photodynamic eradication of bacterial biofilms. Rapid wound dressing and effective antibacterial therapy are of extreme importance for skin wounds treatment in emergency [ 93 , 94 ].
By combing the advantages of in situ electrospinning and AIE PSs, Zhao et al. In their approach, AIEgens TBP -incorporated poly ε-caprolactone PCL solution could be readily electrospun by a handheld electrospinning device to form the nanofibrous dressing, which was closely and well adhesive to the wound surface.
In vitro Fig. Thus, the strategy of in situ deposition of AIE nanofibrous dressing via handheld electrospinning device can provide personalized therapies for emergency wounds with the advantages of convenience, versatility and universality.
AIE materials for bacterial PDT. A Schematic illustration of electrospinning AIEgen TBP-incorporated antibacterial dressing. B Photos of S. C photographs of the appearance of the wounds after different treatments. In addition to explore the applications of AIE PS in different scenarios, researchers also devote a lot to elucidate the relationship of structure and function relationship of antibacterial agents to achieve accurate and efficient antibiosis [ 96 ].
Kang et al. This successful example on structure—activity relationship study could provide guidance for the further exploration of novel antibacterial theranostic agents.
Biofilm-related infections, such as dental plaque and bone implant, have brought great suffering to patients and heavy financial burden to society [ 98 , 99 ]. Bacterial biofilm is a unified community where bacteria are encapsulated by the matrix, leading to the resistance to antibiotics [ ].
PTT has been widely studied as one of the most attractive strategies for combating bacteria with its advantages on light-controllability and hardly no drug resistance [ ]. Recently, He et al. TN NPs were prepared by encapsulation of NIR-absorbing photothermal AIEgens 2TPE-2NDTA with DSPE-PEG Fig.
By taking advantage of active intramolecular motions in the aggregate state and enhanced molar absorptivity, TN NPs showed high ability in photothermal conversion and excellent photobleaching resistance.
The prepared NPs can effectively eliminate mature S. aureus biofilms upon NIR laser by destruction of the adjacent bacteria and deactivation of the adhesive components Fig.
Therefore, PTT is one of the most promising potential candidates for the clinical treatment of biofilm in the future. AIE materials for bacterial PTT. A Schematic illustrations of fabrication of TN NPs by encapsulating DSPE-PEG with 2TPE-2NDTA C Photographs of bacteria colonies grown on NB agar.
D Relative bacterial viability in the treated biofilm of each group. Some AIEgens have been developed with synergistic PDT and PTT effect [ , ]. For instance, Li et al. Under simulated sunlight irradiation, TTVB NM exhibited efficient ROS generation and moderate photothermal conversion performance Fig.
Furthermore, TTVB NM was covered on a medical mask and displayed efficient antimicrobial activity against pathogenic aerosols Fig. It is notable that the filtration efficiency and air permeability of the TTVB NM coated mask showed comparable even better performance than that of other reported antimicrobial wearable materials.
A Schematic illustration of the preparation of TTVB-loaded nanofibrous membrane TTVB NM through electrospinning for microbial inactivation under sunlight.
B ROS generation of TTVB NM under the irradiation of simulated sunlight. C The photothermal conversion performance of NM and TTVB NM under the irradiation of simulated sunlight.
Fungus is a common microorganism widely found in nature, which can lead to various severe infections, like fungal keratitis, fungal dermatosis etc.
The treatment of fungi-related infectious diseases is still challenging because current antifungal drugs suffer drug resistance and side effects.
Recently, some AIEgens with PDT activity are reported as promising candidates for the treatment of fungal infections with the advantages of negligible drug resistance, high spatiotemporal accuracy, and low side effects [ ].
Fungal keratitis is a widespread disease which would cause corneal tissue injury and sight-threatening complication [ ]. Mitochondria is considered as an ideal target for fungi inactivation due to its important role in fungi morphogenesis virulence and drug resistance [ ].
As such, selectively targeting fungal mitochondria is a valuable approach for fungi treatment with low side effects [ ]. Driven by the intrinsic discrepancy in surface membrane potential between fungi and mammalian cells and negative mitochondrial MMP, these cationic AIEgens designed with proper hydrophobicity were expected to preferentially accumulate in the mitochondria of fungi over mammalian cells and cause mitochondrial disruption by PDT effect Fig.
The results indicate that all three AIEgens, especially IQ-TPA, exhibit excellent antifungal activity for in vivo treatment, which is much better than the clinically used PSs rose bengal Fig.
AIE Materials for selective photodynamic killing of fungi. A Molecular structure and B schematic illustration of AIEgens for selective mitochondria-specific PDT of fungi. C Antifungal activity of AIEgens toward C. albicans at different concentrations in the dark and under white light irradiation.
Besides bacterium and fungus, virus is another great threat to public health. There are numerous barriers in the prevention and control of virus-related pandemics due to the lack of specific drugs.
Personal protective equipment PPE , like masks and protective suits, is a key factor to inhibit the spread of virus, preventing healthy people especially frontline healthcare doctors and nurses from virus infection [ ].
In addition, conventional PPEs are usually disposable with limited service life [ ]. Further, the improper disposal of PPEs is likely to cause cross-contamination [ ].
Therefore, there is an emergency to develop self-antiviral PPEs with long-term usable and reusable characteristics. A series of AIE PS based PPEs with real-time self-antiviral capabilities has been successfully reported recently Fig.
For instance, the AIEgen ASCP-TPA was synthesized with the advantages of facile synthesis, excellent biocompatibility and superior ROS generation ability. This strategy shows a great potential to fight against SARS-CoV-2 or other airborne pathogens and to improve global PPE supply shortages.
AIE Materials for self-antiviral PPEs. schematic diagram of the preparation of ASCP-TPA-attached fabrics ATaFs and various ATaF-based PPEs left and the photodynamic inactivation principle of ATaFs against coronavirus upon ultralow-power light irradiation 3.
reproduced from Ref. Multifunctional AIE biomaterials with antiviral and anti-inflammatory abilities is highly desirable. To date, cell membrane-coated nanoparticles NPs have emerged as a biomimetic nanomedicine platform for treatment of different diseases [ ].
Based on this bioinspired strategy, Li et al. The AM membranes endow NPs with function as the coronavirus receptor and multiple cytokine receptors for coronavirus cellular entry and various proinflammatory cytokine binding, respectively, to keep the virus away from their host targets.
After treatment of a surrogate mouse model of COVID caused by murine hepatitis virus A MHV-A with these multifunctional AM-bioinspired NPs under NIR irradiation, not only the virus burden and cytokine levels in lungs decreased but also tissue damage and inflammation were relieved and improved.
Moreover, the viral transmission and infection progress can be restricted after PTT. This work provides an ideal strategy to fabricate novel multifunctional bioinspired NPs with cell membrane-coating method for the effective treatment of COVID Fig. AIE Materials for photothermal disruption of virus.
Schematic illustration of multifunctional AM-like NPs for coronavirus cellular entry blockage, virus photothermal disruption, and inflammatory cytokines absorption.
In addition to photothermal reagents, AIEgens are also utilized for viral photodynamic inactivation. Recently, Wu et al. DTTPB with a hydrophilic head and two hydrophobic tails can selectively bind the envelope of human coronavirus.
These AIEgens could target the viral phospholipid bilayers or protein covering viral capsid via the lipophilic cations of IQ, thus destroy the viral structure under white light irradiation.
This review aims to highlight the latest advances of AIEgens-based biomaterials for theranostics of bacteria, fungi and viruses. Based on the nature of these three pathogens, AIEgens are well modified and thus endowed with the capability of pathogen differentiation and selective imaging.
Integrated with chemotherapeutic activity or phototherapeutic activity, multifunctional AIE biomaterials are developed for efficient pathogen inactivation.
Although AIEgens-based antimicrobial theranostics have made a remarkable progress, there are still much room for improvement. i Visualization of interactions of bacteria—bacteria, microbe—bacteria plays an important role in understanding the corresponding physiological processes. To date, several NIR dyes have been developed for covalent binding with bacteria based on metabolic labeling strategy [ ].
As a result, the endocytosis of bacteria, the interaction of gut microbiota and other dynamic processes could be real-time monitored. ii Artificial intelligent AI assisted pathogen differentiation can significantly improve the accuracy, rapidity and sensitivity, which is highly suitable for high-throughput assay.
iii The back-to-basics principle of new uses of old drugs has emerged as a fruitful basis for the discovery of new AIE drugs [ ].
Thus, some AIE-active natural compounds with advantages of biocompatibility, biodegradability and intrinsic pharmacological activity, have been developed for various applications. iv Biosafety is a frequently discussed topic, which is an essential factor to advance the clinical application. To date, the excretion of AIE NPs in hepatobiliary and gastrointestinal pathway of non-human primates and rodents has been investigated [ ].
Also, the distribution of AIE NPs in different tissue was studied, revealing that AIE NPs have low passive permeability to tumor regions [ ]. More studies on AIE biomaterials, such as bio-distribution and pharmacokinetics, need to be conducted in future.
This work was supported by NSFC , and , Shenzhen Key Laboratory of Functional Aggregate Materials ZDSYS , the Science Technology Innovation Commission of Shenzhen Municipality JCYJ, KQTD, JSGG and GJHZ Dobson AP , Carper ER.
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aeruginosa inhibiting flagella-mediated swimming. Second, it decreases the mRNA level of type IV pili biosynthesis genes at very low concentration, i. aeruginosa that is very much essential for micro-colony formation and colonization during biofilm development.
Third, it downregulates lasI gene encoding for the quorum-sensing molecule acyl-homoserine lactone AHL synthase as well as lasB gene encoding the virulence factors elastase LasB.
In summary, Esc -1c lowers the expression of virulence genes and bacterial motility genes, and ultimately prevents biofilm formation. These two anti-pseudomonal peptides esculentin-1a and its diastereomer Esc -1c have shown promising results in bronchial epithelium repair of cystic fibrosis patients.
Cappiello et al. Besides, the peptide esculentin-1a lowers the expression of mRNA encoding rhamnosyltransferase subunits, i. A recent study by Parducho et al. The melittin peptide of bee venom exhibit antibacterial activity, prevents MRSA systemic infections and initiates the wound healing process in MRSA-infected mice model Choi et al.
Khozani et al. aeruginosa biofilm biomass at 50 μg concentrations during 24 h. Human cathelicidin LL inhibits bacterial adhesion and biofilm mass of S. epidermidis ATCC at a very low concentration Hell et al. In addition to anti-biofilm activity, LL exhibits immunomodulatory activity such as cellular recruitment Tjabringa et al.
The dual property of AMPs to counter bacterial biofilms as well as modulating the host immune system can be exploited to design a novel strategy to combat drug-resistant microbial biofilms.
Parducho et al. aeruginosa biofilm by inducing structural changes, altering outer membrane protein profile and interfering with the transfer of biofilm precursors into the extracellular space. Few natural peptides with anti-biofilm activity and their disadvantages are listed in Table 3. A peptide DRAMP ID: DRAMP derived from the venom of scorpion Tityus obscurus has shown promising anti-biofilm activity against Candida spp.
and Cryptococcus neoformans strains Guilhelmelli et al. These peptides inhibit fungal biofilms at initial adhesion and mature stages, and exhibit minimal hemolytic and cytotoxic activity on erythrocytes and murine peritoneal macrophages.
Pathogens which form the biofilms on the implanted medical devices, human skin, gut, and oral cavities generally communicate through quorum sensing QS signals. The quorum sensing inhibiting potential of AMPs from natural sources offers an alternative antibiotic-free approach to overcome biofilm-associated infections.
To date, more than AMPs have been discovered, but only seven of them have been approved by the FDA Chen and Lu, There is a severe scarcity of clinical studies on natural AMPs due to their poor performance, cytotoxic and hemolytic activities, unpredicted side effects such as kidney injuries, damage to central nervous systems, etc.
The futility of natural AMPs in pre-clinical stages may be due to variations between the clinical setting and their resident conditions. So, clinical research needs to be exaggerated and optimized for the use of these natural anti-biofilm agents against various drug-tolerant biofilms.
It is essential to exploit the structure of different naturally occurring AMPs to develop novel therapeutic peptides with improved stability and activity in comparison with their natural counterparts. Efforts have been made to design novel specifically targeted multi-domain AMPs composed of a species-targeting peptide linked to a broad-spectrum antimicrobial killing peptide domain Sztukowska et al.
C16G2 inhibits the biofilm growth of S. mutans effectively both in pure culture and in a multispecies community Guo et al. This peptide not only kills S. mutans but also reduces other species that are metabolically dependent on S. mutans and mediates the re-establishment of oral microbiome.
This specifically targeted AMP avoids the loss of natural microflora by selectively targeting the pathogens and leaving commensal Streptococci undamaged.
C16G2 has completed a single-blind, open-label phase II clinical trial in various varnish and strip formulations ClinicalTrials. gov Identifier: NCT among female and male dental subjects. Similarly, attempts have been made to target only the pathogenic organisms of the biofilm without influencing the normal microflora Xu et al.
They designed peptides by fusing species-specific enterococcal pheromone cCF10 with a broad-spectrum AMP C6. They proved that incorporation of cCF10 at the N terminus of C6 drastically increased antimicrobial activity against E.
faecalis comparative with C6 alone. They also reported that the hybrid peptides stimulated negligible hemolysis against human RBCs at antimicrobial levels, demonstrating that these fusion peptides could be exploited as potential anti-biofilm agents for clinical implementation.
The failure of conventional antibiotic therapies indicates that biofilm treatments need auxiliary upgradation Zhang et al. Natural anti-biofilm agents selectively exterminate the persistent biofilms and allow the diffusion of antimicrobials into the biofilm matrix. These natural products target various phases of biofilm cycle to degrade the biofilm matrix and finally kills the released cells Figure 3.
A better understanding of the disruption and dispersal mechanism of biofilms will help researchers to design improved anti-biofilm strategies.
Figure 3. The stages of biofilm formation and potential targets for anti-biofilm agents. The bacterial cells in humans attach to the matrix-forming proteins by forming a covalent linkage with peptidoglycan structure or by non-covalent attachment.
With attachment and aggregation of a sufficient number of cells, the formation of EPS matrix takes place, and the attachment now becomes resistant to external repulsive forces. With the maturation of biofilm, the cells within the bulk structure start further communication with each other and start secreting specialized proteins and DNA, and some of them are involved in the formation of the efflux pump.
At last, the dispersion of free planktonic cells from the formed biofilm further promotes the formation of new biofilms in the periphery. The natural anti-biofilm compounds can attack at one or different stages of biofilm formation and development, thus inhibiting it.
A recent study reported that elasnin an anti-biofilm compound from an actinobacteria Streptomyces mobaraensis DSM destroyed the matrix in a multispecies biofilm and making them more vulnerable to antibiotics Long et al.
To improve the current strategies of biofilm inhibition, the concern of the present review is to exploit natural agents for the development of an effective and safe strategy. This review aims to cover some current systems that are being put into practice to disintegrate EPS, quench QS networks, inhibit adhesion, and interrupt biofilm formation Figure 4.
Figure 4. Graphical representation of anti-biofilm strategies covered in this review. EPS targeting: EPS matrix is targeted by matrix-degrading enzymes DNaseI, dispersin B, lysostaphin that inhibit microbial adhesion to a surface.
Quorum sensing targeting: This strategy focused on the use of natural agents that block cell—cell communication in preformed biofilms and regulate virulence factor production Shastry et al. Phage therapy: Engineered phages degrade the matrix exopolysaccharide by producing polysaccharide depolymerase enzymes.
Specially targeted AMPs: This novel strategy targets in a species-specific manner due to the presence of species targeting peptides Xu et al.
Adhesin targeting: Phytocompounds target adhesin proteins and blocked biofilm formation at the beginning Adnan et al. Combination therapy: Natural anti-biofilm agents function effectively in a combined approach in comparison with its single use. Microbial EPSs secreted by a large variety of microorganisms mainly composed of polysaccharides, structural proteins, and extracellular DNA.
The EPS matrix supports microbial adhesion to a surface, aggregation in multilayered biofilms, and functions as a three-dimensional scaffold that provides hydration, digestive capacity, and protection against antimicrobial compounds, antibiotics, and host effecter molecules Flemming et al. The EPS matrix can actively alter nutrient gradients and portray pathogenic environments that contribute to tolerance and virulence traits.
So, many therapeutic strategies are designed to target the EPS matrix to eliminate biofilms, disaggregate bacteria, and interrupt the pathogenic environment. Many bacterial enzymes and secondary metabolites interfere with the quorum sensing mechanisms of pathogenic bacteria, thus disrupting the biofilm formation Khan et al.
Biofilm matrix-degrading enzymes such as beta- N -acetylglucosaminidase and dispersin B secreted by the Gram-negative periodontal pathogen Actinobacillus actinomycetemcomitans disintegrate mature biofilms of Staphylococcus epidermidis.
Cocktail of two EPS-degrading enzymes, DNase I and dispersin B, has been found to inhibit staphylococcal skin colonization and remove pre-attached S. aureus cells from the skin and enhance their povidone-iodine susceptibility in an in vivo pig skin colonization model Kaplan et al.
Hogan et al. Few biofilm-degrading enzymes with their mechanism of biofilm inhibition are summarized in Table 4. The existing enzymes which have less catalytic activity can enhance their catalytic properties against the biofilms by modeling and engineering approach.
The site-directed mutational analysis is considered as another approach to modulate the biofilm-inhibiting properties of the enzymes. The complete elimination of heterogeneous biofilms needs amalgamation of hydrolytic enzymes that can degrade proteins, polysaccharides, eDNA, and QS molecules Yuan et al.
The application of matrix-degrading enzymes in biofilm control is presently limited due to cost, handling procedures, and low industrial accessibility Nahar et al.
Prevention of cell-to-cell communication quorum sensing is an efficient strategy to restrain biofilm formation Sharahi et al. It is reported that metalloprotein AHL-lactonase from the cell-free extract of endophytic Enterobacter species causes degradation of N - AHL, thus significantly inhibiting biofilm formation by Aeromonas hydrophila Shastry et al.
The result of a recent study reported that Lactobacillus crustorum ZHG as novel quorum-quenching bacteria degrade N oxododecanoyl- dl -homoserine lactone 3-oxo-CHSL and N -butyryl- dl -homoserine lactone C4-HSL and functions as an anti-biofilm agent against P. aeruginosa Cui et al. Several quorum quenching QQ enzymes and compounds have been reported.
The majority of these QQ molecules have been isolated from natural sources LaSarre and Federle, The result of a recent study revealed QS inhibitory potentials of ethyl acetate extracts from cell-free supernatants and cells of Natrinemaversi forme against P.
aeruginosa biofilm Başaran et al. Many QS inhibitors from plant-based natural products have been identified Caceres et al. The role of natural anti-biofilm agents in the inhibition of quorum sensing molecules is mentioned in the first part of the review. Here, we attempted to explain their effect on the disruption of QS mechanism.
These anti-biofilm agents disrupt quorum-sensing systems mainly in two ways: 1 inhibition and degradation of signal molecules, and 2 mimicking the signal molecules for inhibition of their binding to corresponding receptors Kalia, On the other hand, quorum quenchers are usually species specific; therefore, a combination of quenchers is required to eliminate mixed-species biofilms.
Ajoene, a sulfur-rich molecule from garlic, decreases the expression of small regulatory RNAs sRNAs in both Gram-negative P. aeruginosa and Gram-positive S. aureus bacteria. Ajoene is the first compound to be identified to target broad-spectrum range quorum sensing inhibitors, i. aureus Scoffone et al.
aeruginosa Jakobsen et al. Ajoene lowered expression of small regulatory RNAs rsmY and rsmZ in P. aeruginosa as a result of which it represses translation of biofilm matrix polysaccharides Pel and Psl and the type VI secretion system T6SS. The T6SS in P. aeruginosa plays an essential role in the expression of various virulence factors and greatly concerned with the biofilm formation, pyocyanin production, and pathogenicity of the organism Li et al.
These findings suggest that T6SS may be a prospective therapeutic target against P. aeruginosa infections. Jakobsen et al. Emodin 1, 2, 8-trihydroxymethyl anthraquinone , an anthraquinone derivative identified from Rheum palmatum Chinese rhubarb and Polygonum cuspidatum Asian knotweed , effectively downregulated luxS gene in Streptococcus suis Yang et al.
aureus Yan et al. The anti-biofilm peptide Human Cathelicidin LL affects the bacterial cell signaling system and inhibits P. aeruginosa biofilm formation at 0. AMPs interact with membranes of bacteria and, in turn, activate genes that are regulated through QS.
These QS autoinducers passed through the plasma membrane with the help of membrane vesicles. This process, in turn, activates the expression of virulence genes associated with QS.
Autoinducers help in interspecies signal transduction; one interesting autoinducer is small autoinducing peptide molecule AIP from Lactobacilli that inhibits the viability of microbes and acts as a suppressor of bacteriotoxin production.
During the process of suppression of exotoxin production, they interfere with the agr QS system Vasilchenko and Rogozhin, However, quorum quenchers can be rinsed away during biofilm formation that makes limited uses of these inhibitors confined to small areas of biofilm only Koo et al.
Thus, combination approach of these inhibitors along with other strategies leads to a novel therapeutic approach.
Lytic bacteriophages have been used as an effective therapeutic strategy to remove biofilm cells. aureus Gharieb et al. Recent investigations have shown that engineered phage-derived enzymes—polysaccharide depolymerase or peptidoglycan-degrading enzymes—are promising therapeutic anti-biofilm candidates Reuter and Kruger, Phage therapy got its first FDA approval in the year in which patients received phage treatment at the School of Medicine, University of California San Diego UCSD phage therapy center Pires et al.
The administration of phage therapy is active only in a few countries, and its clinical use faces many challenges such as the establishment of phage banks with characterized phages; safety, stability, and quality of phage preparations during production; and the evolution of bacterial resistance to phages.
Natural anti-biofilm agents sensitize antibiotics and established to be more effective when used in amalgamation Zhang et al. They also reported that the combined application of sodium houttuyfonate and levofloxacin act in a better manner to inhibit biofilm formation.
Sodium houttuyfonate, a plant-derived anti-neuropeptide, effectively disrupts biofilm dispersion in P. aeruginosa Wang et al. Naringin, a flavanone glycoside extracted from citrus and grapefruits, was found to be more effective against P. aeruginosa biofilms in comparison with individual treatment of marketed antibiotics ciprofloxacin and tetracycline Dey et al.
Naringin depletes biofilm EPS and facilitates the diffusion of antimicrobials, reduces pellicle formation, and decreases the flagellar movement of bacteria on catheter surfaces.
Zhou et al. aeruginosa PAO1 biofilms by a combination of hordenine and netilmicin, which was significantly better than the effect of any of the individual treatments. It indicates that the drug—herb combination therapy may be explored for effective anti-biofilm formulation opportunities.
The SEM study showed a reduction in the thickness of the biofilm layer and the disruption of its architecture. The results of the study also revealed downregulation in the expression of quorum-sensing regulatory genes, especially lasR , by hordenine as the possible mechanism against biofilm development.
Actinobacterial compounds from different microbial species have also shown potential anti-biofilm activity against different pathogenic bacteria by interrupting the cell surface and interaction between cells Azman et al.
Moreover, the selection of a more effective compound is also necessary as the efficacy of natural compounds against biofilm development is different against different strains of bacteria. The adhesion of biofilm-associated pathogenic organisms on implant surfaces restricts their clinical applications, so many attempts have been made by various researchers to coat biomaterial as a preventive strategy.
Natural polymer-based surface coatings, such as anti-adhesive coatings of algal polysaccharide ulvan, dextran, and dermatan sulfate, and antimicrobial-releasing polysaccharide coatings etc. have been popularized during the last decade Junter et al.
A recent report on anti-adhesive CyanoCoating a coating from marine cyanobacterium Cyanothece sp. CCY was exploited as a defensive strategy against a broader range of microbes especially Proteus mirabilis , E.
coli , and C. albicans biofilms in catheter-linked urinary tract infections Costa et al. The molecular mechanism to prevent the cell adhesion is that the hydrophilic polysaccharides form a hydration layer on the surface which acts as a physical barrier Damodaran and Murthy, and prevents cell adhesion to the surface.
Calcium phosphate cement and hydroxyapatite are the calcium phosphate materials that are used as a bone coating to avoid infections of biofilm, but they have various limitations in clinical trials Pan et al.
Implant-related infections can be avoided by chitosan hydrogel coatings which prevent bacterial adhesion and biofilm formation due to membrane leaching Pan et al.
A group of natural polymers were used as drug transporters in various forms like fibers, strips, gels Badam gum, Karaya gum, chitosan , films chitosan , nanoparticles, and microparticles which help in delivering antibiotics to the targeted site mainly for periodontal biofilm-forming pathogens Chi et al.
Nisin, an FDA-approved AMP, acts as anti-biofilm agent synergistically with conventional antibiotics against methicillin-resistant Staphylococcus aureus , Streptococcus pneumoniae , Enterococci , and Clostridium difficile Shin et al.
A recent report stated that nisin in conjugation with gellan gum, a biocompatible polysaccharide, shows promising results in biomaterial research Peng et al. The occurrence of many biofilm-based human infections and their multiple antimicrobial resistance is a major concern in medicine and human health.
The elevated rate of resistance to antibiotics in biofilm leads to the discovery and characterization of novel natural anti-biofilm agents. This review describes different types of phytocompounds, antimicrobial peptides, and biosurfactants that exhibit promising biofilm-inhibiting ability.
Natural anti-biofilm agents could be effectively used to deal with certain surgeries and diseases where there is a possibility of untraceable infection sites like bone, dental, eye lenses, and breast implants.
These agents of natural origin are structurally and functionally more diverse in comparison with conventional antibiotics.
The structure and function of natural anti-biofilm agents from various sources have been exploited to develop numerous advanced therapeutic strategies showing increased activity, stability, and reliability. Here, we continue to analyze the efficacy of specially targeted AMPs against drug-tolerant pathogenic biofilms without disturbing the natural microflora.
Natural products, mainly phytochemicals, as anti-biofilm agents have been studied more in in vitro and in vivo conditions, but not a single FDA-approved drug was developed despite huge efforts. Most of them failed in phase II and phase III clinical trials Lu et al.
The possible reason for this failure may be the availability of the compound in humans after administration which decreases the efficacy of the compounds. One possible solution to this problem is a combination of strategies like antibiotics, along with natural anti-biofilm agents for better results.
Combination therapy of natural agents with commercial antibiotics needs urgent exploitation in the future to advance anti-biofilm activity. Quorum quenchers of natural origin along with antibiotics can be a novel lead for species-specific biofilm destruction, and it has a promising utilization aspect in biomedical industries.
More studies should be directed in this regard for converting the novel anti-biofilm phytocompounds into drugs. Further studies in in vivo models and clinical trials are needed to test the efficiency of natural anti-biofilm agents in the future. The review also explains the quorum quenching molecules and EPS-degrading enzymes of natural origin along with their mode of action on various biofilms.
The mechanism of action of various natural agents against biofilm remains unknown. More studies on the mode of action may help to identify novel anti-biofilm agents. Anti-adhesin strategy can be a novel strategy for biofilm treatments on a broad range of bacteria as it targets and prevents attachment of bacteria to the cell surface.
Very few studies have been made in this area, so future research in targeting biofilm in the direction of adhesin proteins may lead to the discovery of unique natural anti-biofilm agents.
Pili and curli gene expression regulating phytocompounds can control biofilm formation. More work in these directions or a combination of phytocompound which has anti-adhesin properties may be a better therapeutic strategy for biofilm-related ailments.
The failure of natural medicines in clinical trials can be checked by rigorous quality control. The discovery of accurate markers that are sensitive and stable can resolve the problem and help in better quality control of natural anti-biofilm agents. It is a significant challenge faced by natural product research for the discovery of useful QC markers as natural compounds have a very complex structural lattice Zhang et al.
Drug efficacy of natural compounds is mainly based on network pharmacology methods. As a result, more research in this direction can enhance success rate in clinical trials at the final stage. Novel natural anti-biofilm agents in therapeutics may be possible if rigorous studies will be done in quality control, pharmacokinetic and pharmacodynamic co-relationships PK—PD , and PK—PD interactions with metabolomics of host for evaluation of safety and efficacy of the drug.
AP, RM, SD, MS, and SS drafted the manuscript. AP, RM, and JK were responsible for preparing the tables and figures in the manuscript. AP and RM equally contributed to the development of this manuscript. SS assisted to revise the manuscript.
All the authors read and approved the final manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The authors gratefully acknowledge Prof. Hans-Curt Flemming, Biofilm Centre, Faculty of Chemistry, University of Duisburg-Essen, Essen, Germany, and Visiting Professor, Singapore Centre for Environmental Life Sciences Engineering SCELSE , Singapore for his invaluable conceptual and technical advice to this work.
AHL, acyl-homoserine lactone; AMP, anti-microbial peptide; BFC, biofilm-forming capacity; CLSM, confocal laser scanning microscopy; CSH, cell surface hydrophobicity; eDNA, extracellular DNA; EPS, extracellular polymeric substances; GA, ginkgolic acid; HSL, homoserine lactone; MBIC, minimum biofilm inhibitory concentration; MFC, minimal fungicidal concentration; MIC, minimum inhibitory concentration; PMNs, polymorphonuclear leukocytes; QS, quorum sensing; SEM, scanning electron microscopy; TEM, transmission electron microscopy.
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De Vos, W.
Mesures pathogens, including bacteria, fungi Anti-pathoten viruses, greatly threaten the global public health. Anti-pathogen measures pathogen Anti-patbogen, early diagnosis and precise treatment are essential to measuges the mortality Low GI weight loss. Anti-pathogen measures this Phosphorus for bone formation, the recent advances meqsures AIE Anti-pathofen for anti-pathogen theranostics are summarized. With the excellent sensitivity and photostability, AIE biomaterials have been widely applied for precise diagnosis of pathogens. Besides, different types of anti-pathogen methods based on AIE biomaterials will be presented in detail, including chemotherapy and phototherapy. Finally, the existing deficiencies and future development of AIE biomaterials for anti-pathogen applications will be discussed. Human society has been plagued by infectious diseases at different stages of development [ 1 ].
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